Obesity is a condition characterized by accumulation of neutral fat in the fat cell after a sustained state of excessive caloric intake over consumed calories, manifested as a notably higher body weight than the standard body weight (Eiji Itagaki, STEP Taisha.Naibunpi, Kaibashobo Inc., 1st Ed., 1998, p. 105). The excess fat accumulation causes diseases, for example, such as insulin resistance, diabetes mellitus, hypertension, and hyperlipidemia. Combined, these factors are known to significantly increase the risk of atherosclerosis onset, and the term “metabolic syndrome” has been used to describe cases associated with such risk factors. Further, neutral fat hyperlipaemia or obesity is known to increase the risk of onset of diseases, for example, such as pancreatitis, liver dysfunction, cancers (including breast cancer, uterine cancer, ovarian cancer, colon cancer, and prostate cancer), emmeniopathy, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity-hypoventilation syndrome (Pickwickian syndrome), and sleep apnea. It is widely known that diabetes often leads to, onset of, for example, such as angina, heart failure, stroke, claudication, retinopathy, failing vision, kidney failure, neuropathy, skin ulcer, and infection [The Merck Manual of Medical Information, 2nd Home Edition, Merck & Co., 2003].
LCE, present in the endoplasmic reticulum of the cell, is a member of enzymes that catalyze the carbon chain elongation reaction of fatty acids having carbon chains of 12 or more carbon atoms, catalyzing the rate-limiting condensation step. In mammals, many of the fatty acids that are synthesized de novo in the body possess chain lengths of 16 to 18 carbon atoms. These long chain fatty acids constitute more than 90% of all fatty acids present in cells. They are important components of cell membranes, and represent the major components of fat tissues, the largest energy storage reservoir in animals. The highest rate of de novo fatty acid synthesis occurs in liver, converting excess glucose in the body into fatty acids. Glycolysis converts glucose into pyruvate, which is converted to citrate in the mitochondria and transported to the cytosol. Cytosolic ATP citrate lyase generates acetyl-CoA, the precursor of fatty acids and cholesterol. Acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) to form malonyl-CoA. The multifunction enzyme fatty acid synthase (FAS) uses malonyl-CoA, acetyl-CoA, and NADPH to elongate fatty acids in 2-carbon increments. The principal end product of FAS in rodents is palmitoyl-CoA, which has a carbon chain of 16 carbon atoms. LCE elongates the carbon chain of palmitoyl-CoA in 2-carbon increments [The Journal of Biological Chemistry, 276(48), 45358-45366, (2001)]. It is known that an excess fatty acid synthesis in the body increases neutral or other fats, causing fat accumulation. For example, a direct association between LCE and obesity is indicated in WO2005/005665 (Patent Document 1). There is also a report that feeding varies the expression level of mouse FACE (LCE) (Matsuzaka T. et al., J. Lipid Res., 43(6):911-920 (2002); Non-Patent Document 1).
LCE is also present in protozoa and nematodes, and its involvement in the proliferation of cells is known. For example, there has been a report that Trypanosoma, a protozoon that causes African trypanosomiasis (more commonly, African sleeping sickness), uses a fatty acid elongation pathway with LCE to synthesize long chain fatty acids, and that the inhibition of the fatty acid elongation reaction in the cell affects the growth of Trypanosoma (Lee S. H. et al., Cell, 126:691-699 (2006); Non-Patent Document 2).
There has been no compound known to possess an LCE inhibiting effect. The 3-substituted sulfonylpiperidine derivative, a compound of the present invention, has phenyl or heteroaryl at position 3 via an amide bond. To date, no compound has been known that has a specific substituent, such as arylamide or heteroarylamide, at position 3, or that forms an azabicyclo ring instead of a piperidine ring, and has a specific substituent, such as arylamide or heteroarylamide, at position 3.    Patent Document 1: A Pamphlet of International Publication 2005/005665    Non-Patent Document 1: J. Lipid Res., 43(6), 911-920 (2002)    Non-Patent Document 2: Cell, 126:691-699 (2006)